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Review
published: 31 March 2017
doi: 10.3389/fimmu.2017.00365
The Maternal Diet, Gut Bacteria, and
Bacterial Metabolites during
Pregnancy influence Offspring
Asthma
Lawrence E. K. Gray1,2, Martin O’Hely1,3, Sarath Ranganathan3,4,5, Peter David Sly6 and
Peter Vuillermin1,2*
1
Barwon Infant Study, School of Medicine, Deakin University, Geelong, VIC, Australia, 2 Child Health Research Unit,
Barwon Health, Geelong, VIC, Australia, 3 Respiratory Diseases, Infection and Immunity Theme, Murdoch Children’s
Research Institute, Parkville, VIC, Australia, 4 Department of Respiratory and Sleep Medicine, Royal Children’s Hospital,
Parkville, VIC, Australia, 5 Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia, 6 Child Health
Research Centre, The University of Queensland, Brisbane, QLD, Australia
Edited by:
David Dombrowicz,
Institut national de la santé et de la
recherche médicale (INSERM),
France
Reviewed by:
Marie Bodinier,
Institut National de Recherche
Agronomique (INRA), France
Duška Tješić-Drinković,
University of Zagreb, Croatia
*Correspondence:
Peter Vuillermin
[email protected]
Specialty section:
This article was submitted to
Nutritional Immunology,
a section of the journal
Frontiers in Immunology
Received: 04 December 2016
Accepted: 14 March 2017
Published: 31 March 2017
Citation:
Gray LEK, O’Hely M, Ranganathan S,
Sly PD and Vuillermin P (2017) The
Maternal Diet, Gut Bacteria, and
Bacterial Metabolites during
Pregnancy Influence Offspring
Asthma.
Front. Immunol. 8:365.
doi: 10.3389/fimmu.2017.00365
This review focuses on the current evidence that maternal dietary and gut bacterial
exposures during pregnancy influence the developing fetal immune system and subsequent offspring asthma. Part 1 addresses exposure to a farm environment, antibiotics,
and prebiotic and probiotic supplementation that together indicate the importance of
bacterial experience in immune programming and offspring asthma. Part 2 outlines
proposed mechanisms to explain these associations including bacterial exposure of
the fetoplacental unit; immunoglobulin-related transplacental transport of gut bacterial
components; cytokine signaling producing fetomaternal immune alignment; and immune
programming via metabolites produced by gut bacteria. Part 3 focuses on the interplay
between diet, gut bacteria, and bacterial metabolites. Maternal diet influences fecal bacterial composition, with dietary microbiota-accessible carbohydrates (MACs) selecting
short-chain fatty acid (SCFA)-producing bacteria. Current evidence from mouse models
indicates an association between increased maternal dietary MACs, SCFA exposure
during pregnancy, and reduced offspring asthma that is, at least in part, mediated by the
induction of regulatory T lymphocytes in the fetal lung. Part 4 discusses considerations
for future studies investigating maternal diet-by-microbiome determinants of offspring
asthma including the challenge of measuring dietary MAC intake; limitations of the existing measures of the gut microbiome composition and metabolic activity; measures of
SCFA exposure; and the complexities of childhood respiratory health assessment.
Keywords: microbiome, respiratory, short-chain fatty acids, diet, maternal, offspring, asthma
INTRODUCTION
The human microbiome and its host form a complex symbiosis, and the gut microbiome is the primary interface for this relationship, harboring the most diverse array of microorganisms found in the
human body (1). This diversity has been dramatically altered by diet and the modern environment (2).
Changes in the human microbiome may be contributing to the rise of non-communicable diseases in
developed societies, including childhood respiratory diseases such as asthma. These conditions pose
a major health burden and have lifelong effects, with childhood asthma and poor early lung growth
associated with respiratory disease in adulthood (3).
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There is growing evidence that the maternal diet and gut bacteria influence offspring immune function and respiratory health
(4). A number of mechanisms have been identified to explain
the transplacental effects of maternal bacteria on the developing
fetal immune system. These include bacterial exposure of the
fetoplacental unit; immunoglobulin-related transplacental transport of gut bacterial components; cytokine signaling producing
fetomaternal immune alignment; and immune programming via
metabolites produced by gut bacteria. The role of gut bacteria and
their metabolites in the development of fetal immune tolerance
and subsequent offspring asthma is of particular interest.
Maternal gut bacteria are influenced by maternal diet, particularly intake of certain fibers and carbohydrates that have
been collectively termed microbiota-accessible carbohydrates
(MACs). Short-chain fatty acids (SCFAs) are the major metabolite produced by the gut bacteria from MACs. There is compelling
evidence from mouse models linking variations in maternal
dietary intake of MACs, gut bacteria, and SCFA production in
the development of offspring asthma. These findings are yet to
be confirmed in human studies. The aims of this review are to
assess the current evidence regarding the influence of maternal
dietary MACs and gut bacterial exposures during pregnancy on
the developing fetal immune system and subsequent offspring
asthma and discuss the considerations for future studies in this
emerging field.
Amish and Hutterite groups in the United States, both isolated
agrarian communities of genetically similar European descent.
Differences between the groups were correlated with farming
practices, with high dairy farm and livestock exposure in the
Amish associated with lower incidence of asthma and allergic
sensitization (14).
There is evidence that the “farm effect” (12) is not confined to
childhood but acts on the developing fetal immune system during pregnancy. A farming environment has been associated with
increased number and efficiency of regulatory T lymphocytes
(Tregs) (15) as well as an altered cytokine profile in cord blood
(16). Finally, the PASTURE study has demonstrated that maternal exposure to a farming environment is associated with reduced
offspring asthma, although this effect is enhanced by early-life
farm exposure (17). The “farm effect” provides strong evidence
that maternal bacterial exposure during pregnancy influences the
fetal immune system and subsequent risk of offspring asthma.
Prebiotic and probiotic supplementation during pregnancy
may alter maternal gut bacteria and influence maternal immune
function and offspring asthma. These supplements represent
a growing worldwide industry worth billions of dollars (18),
despite insufficient evidence of their purported benefits in many
cases (19). A prebiotic is a “selectively fermented ingredient that
allows specific changes, both in the composition and/or activity
in the gastrointestinal microbiota thus conferring benefit …”
(20). The short-chain galactooligosaccharides (scGOS) and longchain fructooligosaccharides (lcFOS) are human milk oligosaccharides that have attracted research interest for their potential
use in infant formula. Prebiotic human milk oligosaccharides
have immune-modulating effects. Acidic milk oligosaccharides
can alter the production of many cytokines (21), and scGOS/
lcFOS have been shown in other allergic and autoimmune
conditions to act via galectin-9 to suppress immune responses,
promoting interferon-gamma production by T-helper 1 (Th1)
cells and inducing Tregs (22–24). The galectins and other glycanbinding receptors in the intestinal epithelium such as C-type
lectins and siglecs are important potential immune modulators.
These receptors bind many glycans including the human milk
oligosaccharides and other carbohydrates and are implicated in
the putative benefits of prebiotic supplementation (25). scGOS/
lcFOS supplementation during pregnancy may also alter the
fecal microbiome, promoting an increase in maternal bifidobacteria (26). There is preliminary evidence that increased maternal
exposure to scGOS/lcFOS in pregnancy may be associated with
reduced offspring wheeze. Hogenkamp et al. supplemented the
feed of Balb/c mice with scGOS/lcFOS during pregnancy, then fed
offspring with a normal diet, and observed lower lung resistance
in response to methacholine challenge (27). In humans, scGOS/
lcFOS have been shown to reduce recurrent wheeze in high-risk
children supplemented from birth (28); however, similar effects
on offspring of mothers supplemented during pregnancy have
not been reported, and the comprehensive 2016 World Allergy
Organization review found a lack of evidence to support the use
of prebiotics during pregnancy (20).
Probiotics are products containing live microbes designed
to confer a health benefit. Studies of Lactobacillus rhamnosus
GG supplementation demonstrated maternal and infant fecal
PART 1
Evidence that Maternal Bacterial
Exposures during Pregnancy Are
Associated with Offspring Asthma
Maternal exposure to a farming environment during pregnancy
is associated with diverse bacterial experience and reduced risk
of asthma in offspring (5). In the Protection against AllergySTUdy in Rural Environments (PASTURE) study, von Mutius
et al. measured levels of bacterial endotoxin in the home of
farming and non-farming families, demonstrating that higher
exposure was associated with reduced asthma incidence (6). The
Prevention of Allergy Risk factors for Sensitization In children
related to Farming and Anthroposophic Lifestyle (PARSIFAL)
(7) and the Multidisciplinary Study to Identify the Genetic and
Environmental Causes of Asthma in the European Community
Advanced Study (GABRIELA) (8) are two important European
cohorts comparing children living on farms with those living in
suburban areas. Both the PARSIFAL and GABRIELA cohorts
showed an association between a farming environment and
increased bacterial prevalence in mattress dust (9, 10). Ege et al.
reported results from both cohorts, identifying that children living on farms had a lower prevalence of asthma and other atopic
disease in comparison to those from suburban areas (11). Further
analysis of these studies has indicated that the effect on asthma is
largely explained by exposure to cows, straw, and consumption of
raw cow’s milk (12); although unspecified, livestock exposure is
also associated with a lower prevalence of asthma (13). The effect
of a farming environment and livestock exposure on asthma has
been supported by recent evidence comparing children from the
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Maternal Bacteria Influence Offspring Asthma
colonization with the strain (29, 30), although the small number
of subjects in each trial limits the generalizability of these findings. A recent meta-analysis of studies in healthy adults found
a lack of evidence for an effect of probiotic supplementation on
fecal microbiota (31). There is evidence suggesting that probiotic supplementation influences the maternal immune system.
A study of Lactobacillus casei DN11401 supplementation during
pregnancy found an association between supplementation and
changes in maternal serum natural killer cells and decreased
breast milk tumor necrosis factor alpha (32). Other studies
have demonstrated changes in breast milk cytokines following
probiotic supplementation (33). Despite evidence of alterations
in fecal bacteria and effects on immune development, several
clinical trials (33–44) and a well-conducted meta-analysis (45)
have not found an association between probiotic supplementation in pregnancy and childhood asthma. The major limitation
of trials of probiotic supplementation during pregnancy is that
supplementation is not commenced until late in pregnancy, after
a critical window of fetal immune development (46). The results
of a planned trial of supplementation with L. rhamnosus HN001
from the first trimester of pregnancy (47) may provide clearer
evidence for associations between probiotic supplementation in
pregnancy, fetal immune development, and offspring asthma.
Antibiotic use is associated with alterations in fecal bacteria
and increased risk of asthma. Antibiotics rapidly alter fecal
bacteria in adults and children, thereby leading to reduced
richness and diversity (48, 49). A Finnish cohort study of 236
children found macrolide antibiotic use was associated with
alterations in specific bacterial phyla, with a reduction in phylum
Actinobacteria and an increase in phylum Bacteroidetes (50).
Reductions in bacterial richness were found to persist for more
than 2 years after exposure. This study also demonstrated that
early macrolide use was associated with subsequent increased
risk of asthma. An increased risk of asthma following childhood
antibiotic use has also been reported for cephalosporins (51) and
for antibiotics in the International Study of Asthma and Allergies
in Childhood Phase III study (52). Maternal antibiotic use during
pregnancy may influence offspring asthma. A study utilizing the
West Midlands General Practice Research Database, a large birth
cohort of 24,690 children, demonstrated an association between
maternal antibiotic use during pregnancy and increased risk of
allergic disease, with two or more courses of antibiotics during
pregnancy carrying a hazard ratio of 1.68 for offspring asthma
(53). This finding has since been supported in large studies using
the Copenhagen Prospective Study on Asthma in Childhood
(COPSAC) cohort and the Danish Birth Registry, which demonstrated that maternal antibiotic use during pregnancy was associated with a dosage-related increase in risk of offspring asthma
(54–58). There is clear evidence that maternal antibiotic use in
pregnancy leads to altered fecal bacterial phyla, reduced fecal
bacterial species diversity, and increased risk of offspring asthma.
Summary of evidence in this section is found in Table 1.
TABLE 1 | Evidence that maternal bacterial exposures during pregnancy are associated with immune programming and offspring asthma.
Bacterial exposure
Result category
Result
Reference
Farm effect
Bacterial exposure
Increased endotoxin exposure in house
Protection against Allergy-STUdy in
Rural Environments study (6)
Increased bacterial prevalence in mattress dust
Prevention of Allergy Risk factors for
Sensitization In children related to
Farming and Anthroposophic Lifestyle
(7, 9); Genetic and Environmental
Causes of Asthma in the European
Community Advanced Study (8, 10)
Fetal immune
programming
Alterations in cord blood cytokines
(16)
Increased regulatory T lymphocytes (Tregs)
(15)
Asthma
Decreased childhood asthma
(5) (review), (11, 14)
Decreased offspring asthma
(17)
Fecal microbiome
Maternal supplementation associated with increased bifidobacteria
(26)
Immune function in
other autoimmune
conditions
Increased T-helper 1 interferon-gamma production
Treg induction
(23, 24)
Asthma
Maternal supplementation associated with improved offspring lung function
in mice
(27)
Supplementation in infants from birth associated with decreased childhood
wheeze
(28)
Maternal transfer of colonization to offspring
(29, 30)
No maternal transfer of colonization
(31) (meta-analysis)
Immune function
Alterations in breast milk cytokines
(32, 33)
Asthma
No associations found maternal supplementation with offspring asthma
(45) (meta-analysis)
Fecal microbiome
Reduced richness and diversity
(48–50)
Asthma
Childhood use associated with increased childhood asthma
(50–52)
Maternal use during pregnancy associated with increased offspring asthma
(53, 56)
Prebiotic short-chain
galactooligosaccharides/
long-chain
fructooligosaccharides
Probiotics
Antibiotics
Fecal colonization
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(22, 24)
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PART 2
pregnancy. Humanized mouse mothers were orally inoculated
with a labeled strain of Enterococcus faecium from human breast
milk, and the organism subsequently cultured from amniotic
fluid (62) and offspring meconium (63). Bacterial genetic material has also been recently identified in the human placenta (59),
although this finding was questioned on the basis of low read
counts and possible contamination with environmental bacteria
at the time of collection (64). Bacteria have not been successfully
cultured from the placenta to date (65). The presence of bacterial genetic material at these sites remains an important finding,
with evidence that bacterial DNA may be sufficient to effect fetal
immune modulation. Unmethylated CpG motifs in bacterial DNA
have been demonstrated to exert immunostimulatory effects via
toll-like receptor (TLR) 9 (66, 67). TLRs are expressed in many
leukocytes and have an established role in innate immune stimulation (68). TLRs are also important in adaptive immunity, with
dendritic cells releasing regulatory cytokines in response to TLR
binding to promote a Th1 phenotype (68) and a number of TLRs
identified on Tregs including TLRs 4, 5, 7, and 8 (69). Early and
persistent exposure of the fetoplacental unit to maternal bacteria
and bacterial genetic material during pregnancy is likely to be an
important mechanism of fetal immune programming. This effect
may be enhanced by mechanisms described below that increase
transplacental transport of bacterial components, cytokines, and
bacterial metabolites.
Putative Mechanisms for Maternal Gut
Bacterial Influence on Immune
Programming and Offspring Asthma
(Figure 1)
Fetoplacental Microbiome
Bacteria have been identified throughout the fetoplacental unit
that may interact with the developing fetal immune system.
Chorioamnionitis, an infection of the placenta, membranes, or
amniotic fluid associated with prolonged rupture of the membranes, is a cause of preterm birth and neonatal infection. Until
recently, this condition was thought to indicate bacterial invasion
of previously sterile tissues. Evidence of bacterial colonization has
now been found in the placenta (59), placental membranes (60),
amniotic fluid (61), and cord blood (62). Bacterial genetic material
has been identified in the placental membranes of preterm and
term deliveries with and without prior labor, indicating bacterial
colonization of these tissues prior to delivery (60). Bacteria may
colonize the fetoplacental unit early in pregnancy, as bacterial
genetic material has been identified in the amniotic fluid following amniocentesis (61), although bacteria have not been cultured
from this site in humans. Evidence from mice indicates that meconium and cord blood may also be colonized with bacteria during
FIGURE 1 | Mechanisms by which maternal bacteria may influence fetal immune development.
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Maternal Bacteria Influence Offspring Asthma
Maternal Immunoglobulin G (IgG)-Bound Bacterial
Components
TABLE 2 | Putative mechanisms for maternal gut bacterial influence on
immune programming and offspring asthma.
Transplacental transport of gut bacterial components bound
to maternal immunoglobulin influences the developing fetal
immune system and reduces inflammatory responses in offspring.
Studies in mouse models have demonstrated that transplacental
transport of allergen-specific IgG is associated with reduced
offspring asthma (70). There is now evidence to support transplacental transport of bacterial components bound to maternal
IgG. Gomez de Aguero et al. transiently colonized the gut of
a pregnant germ-free mouse with a modified strain of E. coli
HA107 that could not persist, returning the mice to a germ-free
state prior to delivery (71). They observed no changes in offspring
adaptive immune cell numbers but found increases in intestinal
innate lymphoid and mononuclear cells, suggesting that even
transient colonization was linked to fetal immune modulatory
effects. Serum from transiently infected mothers was transferred
to unexposed pregnant mothers, with a subsequent increase in
offspring intestinal innate lymphoid cells. When the serum was
depleted of IgG prior to transfer, this effect was lost, indicating
the importance of IgG-mediated transfer of bacterial components. An increase in intestinal mononuclear cells was observed
in offspring regardless of serum IgG depletion, suggesting that
antibody-mediated transfer is part of a group of transplacental
signals responsible for fetal immune programming.
Description
Reference
Fetoplacental
microbiome
Bacteria present throughout the
fetoplacental unit
(59), (64)
(placenta),
(60) (placental
membranes), (61)
(amniotic fluid),
(62) (cord blood)
Immunostimulatory effects of bacterial
DNA
(66, 67)
Transplacental transport of bacterial
components from modified E. coli in
mice
(71)
Maternal
immunoglobulin
G-bound bacterial
components
Fetoplacental
Correlation between regulatory
immune alignment T lymphocytes (Tregs) and interleukin-10
in mother–child dyads
(72)
Short-chain fatty
acids
Tolerogenic immune state
(90–95)
Increased Treg population and function
(103–106)
Offspring asthma
(108)
PART 3
Evidence that Maternal Diet and Bacterial
Metabolites during Pregnancy Influence
Offspring Asthma
Fetoplacental Immune Alignment
Transplacental cytokine signaling promotes maternal–fetal
immune alignment. Santner-Nanan et al. examined serum from
parents and their offspring, comparing the percentage of peripheral Tregs at term in mother–child dyads with that in father–child
dyads (72). A high correlation was found between mother–child
dyads but not father–child dyads. A high correlation was also
identified for interleukin (IL)-10 levels, as well as an upregulation
of IL-10 receptor alpha in the mother–child dyads, suggesting
that the mechanism for Treg alignment is transplacental signaling by IL-10. Cytokine signaling appears to be another important
mechanism influencing the developing fetal immune system.
Diet Influences Fecal Bacterial Composition
Short-term dietary change alters fecal bacterial composition
rapidly, but reversibly, while long-term dietary change is associated with irreversible alterations. Subjects fed either a plant or
animal-based diet exclusively for 5 days had alterations in fecal
bacterial composition, with an animal-based diet leading to a
relative reduction in bacteria from phylum Firmicutes (78). This
change was rapid, occurring within the first day of a new diet;
however, fecal bacteria reverted its original composition 2 days
after ceasing. This finding is supported by other human studies
indicating short-term dietary changes have temporary effects
on fecal bacterial composition (79). However, elegant work by
Sonnenburg et al. has suggested that long-term dietary change
may alter fecal bacterial composition irreversibly (80). Mice
were fed restricted diets across several generations, demonstrating increased loss of bacterial diversity with each successive
generation. Bacterial diversity loss was only partly reversible
with a return to a broader diet. These findings are consistent
with changes in fecal bacterial composition identified in modern
industrialized societies. Studies in humans comparing the fecal
bacteria of hunter–gatherer with modern societies have consistently found increased microbial diversity in the hunter–gatherer
groups, considered to reflect differences in dietary staples (2, 81,
82). Nakayama et al. have recently demonstrated that a widespread geographic distribution of populations is not required
for these differences to emerge (83). Fecal bacterial composition
in children from different Asian countries was analyzed, and
associations were identified between fecal bacterial composition
Maternal Gut Bacterial Metabolites
Transplacental action of gut bacterial metabolites influences many
host functions, including fetal immune development. Gut bacteria produces numerous metabolites that are critical mediators of
host function, influencing processes such as immune modulation, inflammation, epigenetic changes, and energy production
(73, 74). SCFAs derived from MACs are a key group of metabolites involved in immune modulation and have attracted much
research attention. The three most common SCFAs produced in
the gut are acetate, propionate, and butyrate (75), of which the
majority are butyrate. SCFAs are produced in abundance as a
by-product of bacterial carbohydrate fermentation and are a key
energy source for the human host, supplying approximately 10%
of total energy requirement (76). Further discussion of SCFAs in
fetal immune development and subsequent offspring asthma is
detailed in Part 3 of this review (77).
Summary of evidence in this section is found in Table 2.
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Putative
mechanism
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Maternal Bacteria Influence Offspring Asthma
and either regional or national dietary differences. Differences in
fecal bacterial composition were also found between rural and
metropolitan populations within Thailand, with the authors proposing that differences in dietary fruit intake may explain these.
Evidence from mouse and human studies has demonstrated that
diet influences fecal bacterial composition. Dietary changes that
affect fecal bacterial composition may also affect the production
of bacterial metabolites such as SCFAs.
Short-chain fatty acids are produced by the fermentation of
MACs. MACs may be consumed in the host diet, produced by
the host or by other bacteria. The bulk of these carbohydrates
are found in dietary fiber that resists digestion by the host,
although MACs are found in small amounts in many foods (84).
A proportion of MAC is also derived from the mucous layer of
the gut, a key bacterial substrate in periods of low dietary MAC
availability (85, 86). Until recently, studies have used the terms
dietary fiber or fermentable fiber as a catchall to describe this
“microbiota food” (86); however, this terminology is problematic.
First, it assumes the presence of the appropriate microbial species
to perform the fermentation, which may not exist in a limited
bacterial population. Second, it implies that fiber intake is an
adequate surrogate marker of MAC intake; however, total dietary
MAC intake is not currently accurately quantified by dietary
surveys such as the Food Frequency Questionnaire (FFQ) (86).
Finally, there are many other substrates that contribute these
carbohydrates that are not considered fibers, such as resistant
starches or human milk oligosaccharides (84). To address these
difficulties, Sonnenburg et al. have proposed the term MAC (80,
87). This is preferred as it does not have an implied link to total
dietary fiber and highlights the importance of these substrates in
determining the gut bacterial species mix (87).
Increased dietary MACs promote a gut microbiome characterized by SCFA-producing bacteria and increased fecal
SCFAs. In their landmark study, De Filippo et al. compared
the fecal bacterial composition of children living in a village in
Burkina Faso with the fecal bacterial composition of a group of
Italian children (88). The Burkina Faso village was chosen for
its similarity to a pre-agrarian, hunter–gatherer society, whose
high dietary fiber intake closely resembled that of the Neolithic
period prior to widespread cultivation of food. Feces from
children in the African group had markedly increased phylum
Bacteroidetes and reduced phylum Firmicutes in comparison to
European counterparts. De Fillipo et al. also indicated that the
high-fiber diet of the Burkina Faso group was associated with
increased fecal SCFAs, with a fourfold increase in fecal butyrate
and propionate. Analysis of fecal bacterial composition of other
hunter–gatherer populations in Malawi and Venezuela has found
a high number of bacterial genes associated with digestion of
MACs (81). Following on from these observational studies,
in vitro experiments with a model human colon populated
with fecal bacteria have demonstrated an association between
increased proportions of genus Bacteroides and Prevotella (both
from phylum Bacteroidetes) and propionate concentrations (89).
Diet influences fecal bacterial composition, with a diet high in
MACs associated with increased SCFA-producing phyla and
increased fecal SCFAs.
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SCFAs Produced by Maternal Gut Bacteria Influence
Fetal Immune Development and Offspring Asthma
Short-chain fatty acids produced by maternal gut bacteria
indirectly influence T lymphocytes to produce a tolerogenic
immune environment in the offspring. SCFAs bind three G
protein-coupled receptors [also termed free fatty acid receptors
(FFARs)], GPR41/FFAR3, GPR43/FFAR2, and GPR109a (niacin
receptor), of which only GPR43 is specific to leukocytes. SCFAs
influence neutrophils and eosinophils by binding GPR43 (90) and
through direct inhibition of histone deacetylase (HDAC), resulting in apoptosis (91). Butyrate and propionate have been shown
separately to regulate dendritic cell function by this mechanism,
reducing stimulation of T lymphocytes (92, 93), and the same
pathway was found to operate in colonic inflammatory responses
(94). Butyrate also stimulates the niacin receptor GPR109a with
GPR109a-deficient mice exhibiting reduced IL-10-producing
T lymphocytes (95).
Regulatory T lymphocytes produce a tolerogenic immune
profile and promote a Th1 phenotype protective against the
development of asthma (96). Traditionally, the adaptive immune
system was described as either Th1 or Th2 dominant, with asthma
associated with the Th2 phenotype. The Th2 phenotype is associated with increased IgE production, eosinophilia, and production
of cytokines IL-4, IL-5, IL-9, and IL-13 (97). These cytokines
activate an allergic inflammatory response to encountered aeroallergens and infections that produces the symptoms of asthma
(98). Early studies identified a reduced population of serum
Tregs in asthmatic patients (99, 100). Mouse models of allergic
airways inflammation have shown that introduced Tregs inhibit
disease development and suppress established disease (101). A
key mechanism for Treg-mediated immune modulation and Th1
skewing is the transcription factor forkhead box p3 (Foxp3). In
the presence of allergenic stimulation, Treg cells expressing high
amounts of Foxp3 produce IL-10 and transforming growth factor
beta, suppressing the activity of dendritic cells and other T-cells
and subsequently reducing allergic responses (102).
Short-chain fatty acids directly influence Treg population and
function. Acetate and propionate promote colonic Treg production with an associated increase in Foxp3 and IL-10 expression
in these cells (103). This effect is mediated through inhibition of
HDAC, resulting in increased acetylation of Foxp3 and associated
increased stability and expression at cell surfaces. This mechanism
has been identified in other studies in which mice fed butyrate
and propionate increased the number of extrathymic (104) and
colonic Tregs (105). SCFAs have both indirect and direct effects
on T lymphocytes promoting a tolerogenic immune profile, with
increased Treg populations and activity (106).
Mouse models have demonstrated an association between
increased maternal dietary MACs, SCFA exposure during
pregnancy, and reduced offspring asthma. Trompette et al. and
Thorburn et al. demonstrated that increased maternal dietary
MACs were associated with reduced severity of allergic airway
inflammation in offspring (107, 108). Trompette et al. reproduced
the mechanism of SCFA action through GPR43 and associated
changes to dendritic cell population and T lymphocyte activity
(107). The study by Thorburn et al. was unique in finding that
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Maternal Bacteria Influence Offspring Asthma
pregnant mice exposed to a high MAC diet or acetate have
offspring that appear protected from developing allergic airways
disease and that this effect persists into adulthood (108). A
follow-up small human component (n = 61) of the same study
showed an association between reduced recalled maternal dietary
fiber intake and reduced serum acetate levels. A separate component (n = 40) showed an association between serum acetate
below median level and increased doctor visits for cough/wheeze
and wheeze in offspring in the first year, although a reverse trend
appears for the other SCFAs measured. The author’s choice of
respiratory health outcome in the human components is notable.
Two or more episodes of GP reported cough in the first year may
be associated with maternal serum acetate but is unlikely to yield
a distinct clinical phenotype that is predictive of subsequent risk
of asthma (108). In demonstrating an association between maternal dietary MACs, antenatal exposure to SCFAs, and offspring
asthma, these mouse experiments have suggested a possible target for interventions to reduce the burden of respiratory illnesses
such as asthma; however, further human studies are required.
and higher offspring forced expiratory volume in 1 s (FEV1) at
5 years (124). Maternal exposure to decreased dietary vitamin E
during pregnancy increases offspring cord blood mononuclear
cell proliferation and is associated with reduced offspring wheeze
and improved lung function.
Maternal intake of polyunsaturated fatty acids (PUFAs)
may alter fetal immune development and is associated with
offspring asthma. The most researched group of PUFAs is the
N-3 (omega-3 fatty acids) which may promote a Th1 phenotype
and stimulate Tregs and the N-6 (omega-6 fatty acids), associated with increased inflammation and Th2 skewing (127). It
has been hypothesized that reductions in the ratio of dietary
N-3:N-6 PUFAs in Western societies may be responsible for
an increase in allergic disease (128). Evidence in mice suggests
that maternal PUFAs may influence fetal immune function. van
Vlies et al. fed mice mothers differing ratios of N-3:N-6 PUFAs
and found that both a high and low ratio reduced offspring Th2
response (129). Studies measuring PUFAs in the serum of pregnant women found minimal evidence of an association between
PUFA ratios and childhood respiratory outcomes (130, 131).
Two similar studies by Nwaru et al. and Lumia et al. within the
same study population examined dietary intake of PUFAs and
found conflicting results. Nwaru et al. reported an association
between low PUFA intake and allergic rhinitis but not asthma
in offspring at 5 years (132). Lumia et al. reported an association
between low PUFA intake and asthma at 5 years (133). Oily
fish such as salmon and herring contain increased ratios of
N-3:N-6; however, until recently, trials of supplementation with
fish or fish oil during pregnancy had found only weak evidence
of an association with reduced offspring asthma (134–139). In
2016, Bisgaard et al. reported from the COPSAC cohort that
supplementation with N-3 PUFA during the third trimester of
pregnancy was associated with a relative risk reduction for persistent wheeze or asthma in offspring of 30.7% (140), although
there was no associations found with other allergic outcomes
and the level of supplementation was 15 times greater than the
expected average intake by pregnant mothers (141). Maternal
supplementation with fish-derived N-3PUFAs may alter fetal
immune development and is associated with reduced offspring
asthma.
Summary of evidence in this section is found in Table 3.
Other Maternal Dietary Factors during Pregnancy
Are Associated with Immune-Modulating Effects
and Offspring Asthma
Maternal exposure to increased vitamin D during pregnancy may
influence fetal immune and lung development and reduces offspring wheeze. Vitamin D receptors are found in many immune
cells (109), and early studies showed that vitamin D was able to
promote specific Treg populations (110) as well as numerous
other effects on innate immune pathways (111). The effect of
maternal vitamin D on fetal immune development is less clear
with recent studies finding that high maternal serum vitamin D
associated with decreased Foxp3-expressing Tregs in cord blood
(112). Any association found with offspring asthma is complicated by the effect of vitamin D on fetal lung development, with
low vitamin D associated with reduced lung volumes in mouse
models (113). Evidence from birth cohort studies indicates that
high maternal dietary vitamin D intake is associated with reduced
offspring wheeze (114–117). Recent well-designed, double-blind,
randomized, control studies failed to find a similar association
for vitamin D supplementation, although the control group in
both cases was receiving the recommended daily dose of vitamin
D throughout (118, 119). Maternal vitamin D exposure, either
from diet or supplementation, influences fetal immune and lung
development and the risk of offspring wheeze.
Maternal dietary vitamin E intake influences fetal immune and
lung development and risk of offspring wheeze. Vitamin E has
been found to have effects on many immune pathways, reducing
inflammation (111). Vitamin E has tolerogenic effects on T lymphocytes, reducing their stimulation by interferon-gamma (120)
and promoting their survival (121). Devereux et al. identified that
high maternal dietary intake of vitamin E during pregnancy was
associated with a decreased Th cell proliferative response in cord
blood mononuclear cells (122). Vitamin E intake in pregnancy
has been associated with reduced wheeze in children in a number
of studies (123–126). Vitamin E also has effects on lung function,
with an association between increased maternal vitamin E intake
Frontiers in Immunology | www.frontiersin.org
PART 4
Challenges for Future Research into the
Maternal Diet, Gut Bacteria, Microbial
Metabolites, and Offspring Asthma
There are currently no validated methods to estimate dietary
exposure to MACs. The FFQ is the most widely used measure of
diet in the studies discussed in this review. FFQ allows an estimation of dietary exposures to many specific foods, food groups,
or micronutrients; however, dietary exposure to MACs is more
difficult to estimate. MACs defy traditional categorization into
fibers or carbohydrates due to their ubiquity in small amounts
across a range of foods and food types, and there is currently
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Maternal Bacteria Influence Offspring Asthma
TABLE 3 | Maternal dietary factors during pregnancy associated with immune modulation and offspring asthma.
Dietary factor
Result category
Result
Reference
Vitamin D
Immune function
Vitamin D enhances regulatory T lymphocyte (Treg) activity
(110), (111)
(review)
Fetal immune
programming
Increased maternal serum vitamin D associated with reduced offspring forkhead box p3-expressing Tregs
(112)
Offspring asthma
Increased maternal dietary vitamin D intake associated with reduced offspring wheeze
(114–117)
Maternal vitamin D supplementation not associated with offspring wheeze
(118, 119)
Vitamin E reduces inflammation
(111) (review)
Vitamin E reduces T lymphocyte stimulation by interferon-gamma
(120)
Vitamin E increases T lymphocyte survival
(121)
Fetal immune
programming
Increased maternal dietary vitamin E decreases T helper response in cord blood
(122)
Offspring asthma
Increased maternal dietary vitamin E intake associated with reduced offspring wheeze
(123–126)
Increased maternal dietary vitamin E intake associated with improved offspring lung function
(124)
Fetal immune
programming
Increased and decreased N-3:N-6 PUFA ratio associated with reduced offspring Th2 response in mice
(129)
Offspring asthma
Maternal serum PUFAs not associated with offspring asthma
(130, 131)
Increased maternal dietary PUFAs or supplementation with fish or supplementation with lower dosage of
fish oil not associated with offspring asthma
(132–139)
Maternal supplementation with high dosage of fish oil associated with reduced offspring asthma
(140)
Vitamin E
Polyunsaturated
fatty acids
(PUFAs)
Immune function
no validated method for this estimation (142). Establishing an
accurate estimate of MAC exposure from diet remains the subject
of current research efforts (143) and is critical to investigating any
association between MACs and other outcomes.
Gut bacterial composition is inferred from the fecal microbiome. When assembling this review, we identified a single
prospective study that examined the relationship between maternal fecal bacteria and offspring asthma as its primary outcome.
Lange et al. examined fecal bacteria from 60 mothers during the
third trimester and found evidence of an association between
higher total aerobes and enterococci and infant wheeze (144).
The small study size, use of a culture-dependent method, and
assessment of only very early respiratory outcomes limits the
interpretation of these findings. These limitations do not detract
from the importance of demonstrating an association between
maternal gut bacteria in pregnancy and offspring asthma using a
culture-dependent method. Culture-independent methods based
on bacterial genetic material have largely replaced such studies.
Current studies of gut bacteria use bacterial genetic material
extracted from fecal samples and analyzed using next-generation
techniques to determine a fecal microbiome. The microbiome
is a detailed picture of the species, relative abundance, diversity,
and metabolic functions of all the microbiota present in the gut,
inferred entirely from genetic material collected from feces. There
are two principal approaches to the analysis of the gut microbiome: shotgun metagenomic sequencing and 16S sequencing.
Shotgun metagenomic sequencing extracts all the DNAs from a
fecal sample, fragments it, and sequences on one of several available massively parallel sequencing (MPS) platforms. Resulting
reads are then assembled into longer sequences and aligned to
databases of known and predicted genes, thus inferring the functional potential of the microbiota and giving an approximation of
the taxa present in the sample. At present, this approach suffers
Frontiers in Immunology | www.frontiersin.org
from a high cost per sample; but it is reasonable to think the price
will decline in the next few years.
16S sequencing targets a few hundred bases of a gene believed
to be common to all bacterial species, the 16S ribosomal subunit.
Variability within this gene has been the gold standard for taxonomic classification for bacteria. The selected fragment of 16S
rDNA is extracted from the DNA in a sample, amplified via PCR
and usually ligated to barcode DNA oligomers for multiplex MPS
sequencing. Resulting reads are demultiplexed, clustered into
operational taxonomic units (collections of sequence that satisfy
a similarity criterion designed to avoid spurious variation due
to sequencing errors) and aligned to comprehensive databases of
16S rDNA sequences. 16S sequencing gives a putative taxonomic
profile of the species present in the sample; however, functional
information has to be inferred.
The fecal microbiome is highly likely to be representative of
the gut bacterial composition in the lumen of the lower digestive tract but may not reflect the full complexity of human gut
bacteria and may be contaminated with environmental bacterial genetic material or the genetic material of dead bacteria.
Furthermore, as the fecal microbiome is only a proxy measure
of the gut microbiota, absolute quantitative information is dubious. Relative quantitative comparisons between samples may be
valid, provided samples have been stored and treated uniformly.
Numbers of reads assigned to a taxon should be treated with caution as PCR biases, gene copy number variation, and variability
in regions surrounding the formal “variable” regions can affect
primer efficiency. Software tools comparing the composition of
samples either use straightforward statistical tests for a priori
hypotheses, more sophisticated statistical analyses (usually
derived from techniques used in RNA-seq analysis, and perhaps
sub-optimal for microbiome analysis) for discovery of differential abundances between experimental conditions, or biological
8
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Maternal Bacteria Influence Offspring Asthma
outcomes, or use machine-learning approaches to detect more
subtle patterns among bacterial composition, treatments, and
outcomes. There is currently no consensus in the field as to which
methods represent best practice, and there is substantial scope for
more mature techniques.
Measurement of SCFA production by gut bacteria and SCFA
exposure in humans is challenging. The majority of SCFAs
produced are rapidly consumed by colonocytes. A unique study
by Cummings et al. carried out in cadavers demonstrated that
the concentration of SCFAs, particularly butyrate, significantly
diminishes between the cecum and rectum (145). Colonocyte
consumption of butyrate does not produce a specific marker
or by-product to allow total butyrate consumption during
gut transit to be measured. Colonocyte consumption is also
dependent on cellular energy requirements that vary under
different conditions. Subsequently, fecal SCFAs are a limited
marker of total SCFA exposure. Serum SCFAs are also an inadequate measure of total SCFA exposure. Colonocyte consumption prevents the majority of butyrate reaching the serum and
proportionally more acetate and propionate are found in the
serum. Cummings et al. found significant differences in acetate
and propionate concentrations at different blood sampling sites
with the highest concentrations found in the portal vein and the
lowest concentrations found in the peripheral veins indicating
acetate and propionate are subject to first-pass hepatic metabolism (145). Acetate and propionate are primarily utilized by the
liver in gluconeongenesis, along with many other substrates.
SCFA utilization in gluconeogenesis does not produce a specific
marker or by-product to allow total acetate and propionate consumption to be measured. Despite these limitations, measures
of SCFAs in feces and serum are currently used to indicate total
host SCFA exposure. Further research is needed into alternate
methods to measure SCFA exposure, and the limitations of
serum and fecal SCFA measurement must be considered when
describing SCFA-related associations.
Defining offspring respiratory health phenotypes that predict asthma that persists into later life may be difficult in infancy
and early childhood. Childhood respiratory health has been
defined using a variety of outcome measures in the studies discussed, including parent-reported symptoms; medication use,
hospital presentations or physician diagnosis; and lung function testing. These measures have not been utilized consistently
and case definitions of wheeze and asthma vary throughout
the studies. Only a small number of studies performed lung
function testing, likely reflecting difficulty in obtaining accurate lung function measures in preschool children. Newer tidal
volume techniques such as Multiple Breath Washout or Forced
Oscillation Testing allow measurement in children from birth
(146). Future studies must carefully consider the respiratory
outcomes chosen and may benefit from tidal volume lung function techniques.
immune system influence offspring asthma. In mouse studies,
these associations have been linked, providing evidence that
dietary MACs select a gut bacterial composition that produces
increased SCFAs. These SCFAs influence T lymphocytes in the
developing fetal immune system to produce a tolerogenic state
that is associated with reduced risk of offspring wheeze and
asthma.
Evidence from farm studies, probiotic supplementation, and
antibiotic exposure has demonstrated the association between
maternal bacterial exposures during pregnancy and offspring
asthma. Maternal bacterial exposure in pregnancy influences the
developing fetal immune system by a number of potential mechanisms including bacterial exposure of the fetoplacental unit;
immunoglobulin-related transplacental transport of gut bacterial
components; cytokine signaling producing fetomaternal immune
alignment; and transplacental action of gut bacterial metabolites
such as SCFAs. Diet is a key determinant of gut bacterial composition and dietary MACs alter fecal bacterial composition to
select SCFA-producing bacteria and influence SCFA production.
There is consistent evidence for SCFA-mediated effects on the
developing fetal immune system; however, an association has not
been reported between maternal dietary MACs or SCFA exposure
during pregnancy and offspring asthma in humans.
Current measures of MACs, gut bacterial composition,
SCFAs, and offspring asthma have limitations. Estimating
exposure to MACs and SCFAs is particularly difficult with the
proxy measures available. The fecal microbiome, although now
nearly ubiquitously used in studies of gut bacteria, must still
be interpreted carefully. Developments in lung function testing
may allow respiratory phenotype and asthma diagnosis to be
more accurately predicted in early childhood, although these
techniques still require further validation. Longitudinal birth
cohort studies measuring maternal diet, gut bacteria, bacterial
metabolite exposures during pregnancy, as well as fetal immune
function and offspring asthma to school age are needed to examine the associations identified in this review. Respiratory health
is determined by a combination of many antenatal and early-life
influences, and it is difficult to predict the relative contribution of
any single influence in isolation. Confounding factors influencing respiratory health should be included in any future study
order to estimate the magnitude of any effects identified. Asthma
is a complex multifactorial condition; however, it appears likely
that dietary MACs, gut bacteria, and SCFAs are potential determinants of offspring health. This research holds out the hope of
simple, cost-effective interventions in pregnancy to reduce the
incidence of offspring asthma.
AUTHOR CONTRIBUTIONS
LG is the primary author. The authors have contributed equally
to the conception and drafting of this review and are accountable
for all aspects.
CONCLUSION
FUNDING
There is evidence that antenatal interaction between maternal
diet, gut bacteria, bacterial metabolites, and the developing fetal
Frontiers in Immunology | www.frontiersin.org
This review is fully funded by Deakin University.
9
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Maternal Bacteria Influence Offspring Asthma
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Conflict of Interest Statement: This review was conducted in the absence of any
commercial or financial relationships, and the authors have no conflict of interest
to declare. LG is a PhD candidate at Deakin University for which he receives a
scholarship from the University. He has internally submitted portions of this work
as part of his Confirmation of Candidature; however, no part of this review has
been previously published.
Copyright © 2017 Gray, O’Hely, Ranganathan, Sly and Vuillermin. This is an open-access article distributed under the terms of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) or licensor are credited and that the original publication in this
journal is cited, in accordance with accepted academic practice. No use, distribution
or reproduction is permitted which does not comply with these terms.
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March 2017 | Volume 8 | Article 365